Publications by authors named "Bernice E Morrow"

76 Publications

Using common genetic variation to examine phenotypic expression and risk prediction in 22q11.2 deletion syndrome.

Nat Med 2020 12 9;26(12):1912-1918. Epub 2020 Nov 9.

Department of Psychiatry, Brain Center, University Medical Center Utrecht, Utrecht, The Netherlands.

The 22q11.2 deletion syndrome (22q11DS) is associated with a 20-25% risk of schizophrenia. In a cohort of 962 individuals with 22q11DS, we examined the shared genetic basis between schizophrenia and schizophrenia-related early trajectory phenotypes: sub-threshold symptoms of psychosis, low baseline intellectual functioning and cognitive decline. We studied the association of these phenotypes with two polygenic scores, derived for schizophrenia and intelligence, and evaluated their use for individual risk prediction in 22q11DS. Polygenic scores were not only associated with schizophrenia and baseline intelligence quotient (IQ), respectively, but schizophrenia polygenic score was also significantly associated with cognitive (verbal IQ) decline and nominally associated with sub-threshold psychosis. Furthermore, in comparing the tail-end deciles of the schizophrenia and IQ polygenic score distributions, 33% versus 9% of individuals with 22q11DS had schizophrenia, and 63% versus 24% of individuals had intellectual disability. Collectively, these data show a shared genetic basis for schizophrenia and schizophrenia-related phenotypes and also highlight the future potential of polygenic scores for risk stratification among individuals with highly, but incompletely, penetrant genetic variants.
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http://dx.doi.org/10.1038/s41591-020-1103-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7975627PMC
December 2020

Optical mapping of the 22q11.2DS region reveals complex repeat structures and preferred locations for non-allelic homologous recombination (NAHR).

Sci Rep 2020 07 22;10(1):12235. Epub 2020 Jul 22.

Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.

The most prevalent microdeletion in humans occurs at 22q11.2, a region rich in chromosome-specific low copy repeats (LCR22s). The structure of this region has defied elucidation due to its size, regional complexity, and haplotype diversity, and is not well represented in the human genome reference. Most individuals with 22q11.2 deletion syndrome (22q11.2DS) carry a de novo hemizygous deletion of ~ 3 Mbp occurring by non-allelic homologous recombination (NAHR) mediated by LCR22s. In this study, optical mapping has been used to elucidate LCR22 structure and variation in 88 individuals in thirty 22q11.2DS families to uncover potential risk factors for germline rearrangements leading to 22q11.2DS offspring. Families were optically mapped to characterize LCR22 structures, NAHR locations, and genomic signatures associated with the deletion. Bioinformatics analyses revealed clear delineations between LCR22 structures in normal and deletion-containing haplotypes. Despite no explicit whole-haplotype predisposing configurations being identified, all NAHR events contain a segmental duplication encompassing FAM230 gene members suggesting preferred recombination sequences. Analysis of deletion breakpoints indicates that preferred recombinations occur between FAM230 and specific segmental duplication orientations within LCR22A and LCR22D, ultimately leading to NAHR. This work represents the most comprehensive analysis of 22q11.2DS NAHR events demonstrating completely contiguous LCR22 structures surrounding and within deletion breakpoints.
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http://dx.doi.org/10.1038/s41598-020-69134-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7376033PMC
July 2020

Gene-based analyses of the maternal genome implicate maternal effect genes as risk factors for conotruncal heart defects.

PLoS One 2020 9;15(6):e0234357. Epub 2020 Jun 9.

Department of Epidemiology, Human Genetics and Environmental Sciences, UTHealth School of Public Health, Houston, Texas, United States of America.

Congenital heart defects (CHDs) affect approximately 1% of newborns. Epidemiological studies have identified several genetically-mediated maternal phenotypes (e.g., pregestational diabetes, chronic hypertension) that are associated with the risk of CHDs in offspring. However, the role of the maternal genome in determining CHD risk has not been defined. We present findings from gene-level, genome-wide studies that link CHDs to maternal effect genes as well as to maternal genes related to hypertension and proteostasis. Maternal effect genes, which provide the mRNAs and proteins in the oocyte that guide early embryonic development before zygotic gene activation, have not previously been implicated in CHD risk. Our findings support a role for and suggest new pathways by which the maternal genome may contribute to the development of CHDs in offspring.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0234357PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7282656PMC
August 2020

Genetic contributors to risk of schizophrenia in the presence of a 22q11.2 deletion.

Authors:
Isabelle Cleynen Worrawat Engchuan Matthew S Hestand Tracy Heung Aaron M Holleman H Richard Johnston Thomas Monfeuga Donna M McDonald-McGinn Raquel E Gur Bernice E Morrow Ann Swillen Jacob A S Vorstman Carrie E Bearden Eva W C Chow Marianne van den Bree Beverly S Emanuel Joris R Vermeesch Stephen T Warren Michael J Owen Pankaj Chopra David J Cutler Richard Duncan Alex V Kotlar Jennifer G Mulle Anna J Voss Michael E Zwick Alexander Diacou Aaron Golden Tingwei Guo Jhih-Rong Lin Tao Wang Zhengdong Zhang Yingjie Zhao Christian Marshall Daniele Merico Andrea Jin Brenna Lilley Harold I Salmons Oanh Tran Peter Holmans Antonio Pardinas James T R Walters Wolfram Demaerel Erik Boot Nancy J Butcher Gregory A Costain Chelsea Lowther Rens Evers Therese A M J van Amelsvoort Esther van Duin Claudia Vingerhoets Jeroen Breckpot Koen Devriendt Elfi Vergaelen Annick Vogels T Blaine Crowley Daniel E McGinn Edward M Moss Robert J Sharkus Marta Unolt Elaine H Zackai Monica E Calkins Robert S Gallagher Ruben C Gur Sunny X Tang Rosemarie Fritsch Claudia Ornstein Gabriela M Repetto Elemi Breetvelt Sasja N Duijff Ania Fiksinski Hayley Moss Maria Niarchou Kieran C Murphy Sarah E Prasad Eileen M Daly Maria Gudbrandsen Clodagh M Murphy Declan G Murphy Antonio Buzzanca Fabio Di Fabio Maria C Digilio Maria Pontillo Bruno Marino Stefano Vicari Karlene Coleman Joseph F Cubells Opal Y Ousley Miri Carmel Doron Gothelf Ehud Mekori-Domachevsky Elena Michaelovsky Ronnie Weinberger Abraham Weizman Leila Kushan Maria Jalbrzikowski Marco Armando Stéphan Eliez Corrado Sandini Maude Schneider Frédérique Sloan Béna Kevin M Antshel Wanda Fremont Wendy R Kates Raoul Belzeaux Tiffany Busa Nicole Philip Linda E Campbell Kathryn L McCabe Stephen R Hooper Kelly Schoch Vandana Shashi Tony J Simon Flora Tassone Celso Arango David Fraguas Sixto García-Miñaúr Jaume Morey-Canyelles Jordi Rosell Damià H Suñer Jasna Raventos-Simic Michael P Epstein Nigel M Williams Anne S Bassett

Mol Psychiatry 2020 Feb 3. Epub 2020 Feb 3.

Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto, ON, Canada.

Schizophrenia occurs in about one in four individuals with 22q11.2 deletion syndrome (22q11.2DS). The aim of this International Brain and Behavior 22q11.2DS Consortium (IBBC) study was to identify genetic factors that contribute to schizophrenia, in addition to the ~20-fold increased risk conveyed by the 22q11.2 deletion. Using whole-genome sequencing data from 519 unrelated individuals with 22q11.2DS, we conducted genome-wide comparisons of common and rare variants between those with schizophrenia and those with no psychotic disorder at age ≥25 years. Available microarray data enabled direct comparison of polygenic risk for schizophrenia between 22q11.2DS and independent population samples with no 22q11.2 deletion, with and without schizophrenia (total n = 35,182). Polygenic risk for schizophrenia within 22q11.2DS was significantly greater for those with schizophrenia (p = 6.73 × 10). Novel reciprocal case-control comparisons between the 22q11.2DS and population-based cohorts showed that polygenic risk score was significantly greater in individuals with psychotic illness, regardless of the presence of the 22q11.2 deletion. Within the 22q11.2DS cohort, results of gene-set analyses showed some support for rare variants affecting synaptic genes. No common or rare variants within the 22q11.2 deletion region were significantly associated with schizophrenia. These findings suggest that in addition to the deletion conferring a greatly increased risk to schizophrenia, the risk is higher when the 22q11.2 deletion and common polygenic risk factors that contribute to schizophrenia in the general population are both present.
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http://dx.doi.org/10.1038/s41380-020-0654-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7396297PMC
February 2020

Atypical chromosome 22q11.2 deletions are complex rearrangements and have different mechanistic origins.

Hum Mol Genet 2019 11;28(22):3724-3733

Department of Human Genetics, KU Leuven, Leuven, Belgium.

The majority (99%) of individuals with 22q11.2 deletion syndrome (22q11.2DS) have a deletion that is caused by non-allelic homologous recombination between two of four low copy repeat clusters on chromosome 22q11.2 (LCR22s). However, in a small subset of patients, atypical deletions are observed with at least one deletion breakpoint within unique sequence between the LCR22s. The position of the chromosome breakpoints and the mechanisms driving those atypical deletions remain poorly studied. Our large-scale, whole genome sequencing study of >1500 subjects with 22q11.2DS identified six unrelated individuals with atypical deletions of different types. Using a combination of whole genome sequencing data and fiber-fluorescence in situ hybridization, we mapped the rearranged alleles in these subjects. In four of them, the distal breakpoints mapped within one of the LCR22s and we found that the deletions likely occurred by replication-based mechanisms. Interestingly, in two of them, an inversion probably preceded inter-chromosomal 'allelic' homologous recombination between differently oriented LCR22-D alleles. Inversion associated allelic homologous recombination (AHR) may well be a common mechanism driving (atypical) deletions on 22q11.2.
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http://dx.doi.org/10.1093/hmg/ddz166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6935389PMC
November 2019

Complete Sequence of the 22q11.2 Allele in 1,053 Subjects with 22q11.2 Deletion Syndrome Reveals Modifiers of Conotruncal Heart Defects.

Am J Hum Genet 2020 01 20;106(1):26-40. Epub 2019 Dec 20.

Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA. Electronic address:

The 22q11.2 deletion syndrome (22q11.2DS) results from non-allelic homologous recombination between low-copy repeats termed LCR22. About 60%-70% of individuals with the typical 3 megabase (Mb) deletion from LCR22A-D have congenital heart disease, mostly of the conotruncal type (CTD), whereas others have normal cardiac anatomy. In this study, we tested whether variants in the hemizygous LCR22A-D region are associated with risk for CTDs on the basis of the sequence of the 22q11.2 region from 1,053 22q11.2DS individuals. We found a significant association (FDR p < 0.05) of the CTD subset with 62 common variants in a single linkage disequilibrium (LD) block in a 350 kb interval harboring CRKL. A total of 45 of the 62 variants were associated with increased risk for CTDs (odds ratio [OR) ranges: 1.64-4.75). Associations of four variants were replicated in a meta-analysis of three genome-wide association studies of CTDs in affected individuals without 22q11.2DS. One of the replicated variants, rs178252, is located in an open chromatin region and resides in the double-elite enhancer, GH22J020947, that is predicted to regulate CRKL (CRK-like proto-oncogene, cytoplasmic adaptor) expression. Approximately 23% of patients with nested LCR22C-D deletions have CTDs, and inactivation of Crkl in mice causes CTDs, thus implicating this gene as a modifier. Rs178252 and rs6004160 are expression quantitative trait loci (eQTLs) of CRKL. Furthermore, set-based tests identified an enhancer that is predicted to target CRKL and is significantly associated with CTD risk (GH22J020946, sequence kernal association test (SKAT) p = 7.21 × 10) in the 22q11.2DS cohort. These findings suggest that variance in CTD penetrance in the 22q11.2DS population can be explained in part by variants affecting CRKL expression.
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http://dx.doi.org/10.1016/j.ajhg.2019.11.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7077921PMC
January 2020

Tbx1 and Foxi3 genetically interact in the pharyngeal pouch endoderm in a mouse model for 22q11.2 deletion syndrome.

PLoS Genet 2019 08 14;15(8):e1008301. Epub 2019 Aug 14.

Department of Genetics, Albert Einstein College of Medicine, Bronx, New York, United States of America.

We investigated whether Tbx1, the gene for 22q11.2 deletion syndrome (22q11.2DS) and Foxi3, both required for segmentation of the pharyngeal apparatus (PA) to individual arches, genetically interact. We found that all Tbx1+/-;Foxi3+/- double heterozygous mouse embryos had thymus and parathyroid gland defects, similar to those in 22q11.2DS patients. We then examined Tbx1 and Foxi3 heterozygous, null as well as conditional Tbx1Cre and Sox172A-iCre/+ null mutant embryos. While Tbx1Cre/+;Foxi3f/f embryos had absent thymus and parathyroid glands, Foxi3-/- and Sox172A-iCre/+;Foxi3f/f endoderm conditional mutant embryos had in addition, interrupted aortic arch type B and retroesophageal origin of the right subclavian artery, which are all features of 22q11.2DS. Tbx1Cre/+;Foxi3f/f embryos had failed invagination of the third pharyngeal pouch with greatly reduced Gcm2 and Foxn1 expression, thereby explaining the absence of thymus and parathyroid glands. Immunofluorescence on tissue sections with E-cadherin and ZO-1 antibodies in wildtype mouse embryos at E8.5-E10.5, revealed that multilayers of epithelial cells form where cells are invaginating as a normal process. We noted that excessive multilayers formed in Foxi3-/-, Sox172A-iCre/+;Foxi3f/f as well as Tbx1 null mutant embryos where invagination should have occurred. Several genes expressed in the PA epithelia were downregulated in both Tbx1 and Foxi3 null mutant embryos including Notch pathway genes Jag1, Hes1, and Hey1, suggesting that they may, along with other genes, act downstream to explain the observed genetic interaction. We found Alcam and Fibronectin extracellular matrix proteins were reduced in expression in Foxi3 null but not Tbx1 null embryos, suggesting that some, but not all of the downstream mechanisms are shared.
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http://dx.doi.org/10.1371/journal.pgen.1008301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6709926PMC
August 2019

Spatiotemporal Gene Coexpression and Regulation in Mouse Cardiomyocytes of Early Cardiac Morphogenesis.

J Am Heart Assoc 2019 08 19;8(15):e012941. Epub 2019 Jul 19.

Department of Genetics Albert Einstein College of Medicine Bronx NY.

Background Heart tube looping to form a 4-chambered heart is a critical stage of embryonic heart development, but the gene drivers and their regulatory targets have not been extensively characterized at the cell-type level. Methods and Results To study the interaction of signaling pathways, transcription factors (TFs), and genetic networks in the process, we constructed gene co-expression networks and identified gene modules highly activated in individual cardiomyocytes at multiple anatomical regions and developmental stages using previously published single-cell RNA-seq data. Function analyses of the modules uncovered major pathways important for spatiotemporal cardiomyocyte differentiation. Interestingly, about half of the pathways were highly active in cardiomyocytes at the outflow tract (OFT) and atrioventricular canal, including well-known pathways for cardiac development and many newly identified ones. We predicted that these OFT-atrioventricular canal pathways were regulated by a large number of TFs actively expressed at the OFT-atrioventricular canal cardiomyocytes, with the prediction supported by motif enrichment analysis, including 10 TFs that have not been previously associated with cardiac development (eg, Etv5, Rbpms, and Baz2b). Furthermore, we found that TF targets in the OFT-atrioventricular canal modules were most significantly enriched with genes associated with mouse heart developmental abnormalities and human congenital heart defects, in comparison with TF targets in other modules, consistent with the critical developmental roles of OFT. Conclusions By analyzing gene co-expression at single cardiomyocytes, our systematic study has uncovered many known and additional new important TFs and their regulated molecular signaling pathways that are spatiotemporally active during heart looping.
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http://dx.doi.org/10.1161/JAHA.119.012941DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6761639PMC
August 2019

Gene-based genome-wide association studies and meta-analyses of conotruncal heart defects.

PLoS One 2019 17;14(7):e0219926. Epub 2019 Jul 17.

Department of Epidemiology, Human Genetics and Environmental Sciences and Human Genetics Center, UTHealth School of Public Health, Houston, Texas, United States of America.

Conotruncal heart defects (CTDs) are among the most common and severe groups of congenital heart defects. Despite evidence of an inherited genetic contribution to CTDs, little is known about the specific genes that contribute to the development of CTDs. We performed gene-based genome-wide analyses using microarray-genotyped and imputed common and rare variants data from two large studies of CTDs in the United States. We performed two case-parent trio analyses (N = 640 and 317 trios), using an extension of the family-based multi-marker association test, and two case-control analyses (N = 482 and 406 patients and comparable numbers of controls), using a sequence kernel association test. We also undertook two meta-analyses to combine the results from the analyses that used the same approach (i.e. family-based or case-control). To our knowledge, these analyses are the first reported gene-based, genome-wide association studies of CTDs. Based on our findings, we propose eight CTD candidate genes (ARF5, EIF4E, KPNA1, MAP4K3, MBNL1, NCAPG, NDFUS1 and PSMG3). Four of these genes (ARF5, KPNA1, NDUFS1 and PSMG3) have not been previously associated with normal or abnormal heart development. In addition, our analyses provide additional evidence that genes involved in chromatin-modification and in ribonucleic acid splicing are associated with congenital heart defects.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0219926PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6636758PMC
March 2020

Copy number variations in individuals with conotruncal heart defects reveal some shared developmental pathways irrespective of 22q11.2 deletion status.

Birth Defects Res 2019 08 20;111(13):888-905. Epub 2019 Jun 20.

Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

Over 50% of patients with 22q11.2 deletion syndrome (DS) have a conotruncal or related cardiac defect (CTRD). We hypothesized that similar genetic variants, developmental pathways and biological functions, contribute to disease risk for CTRD in patients without a 22q11.2 deletion (ND-CTRD) and with a 22q11.2 deletion (DS-CTRD). To test this hypothesis, we performed rare CNV (rCNV)-based analyses on 630 ND-CTRD cases and 602 DS-CTRD cases with comparable cardiac lesions separately and jointly. First, we detected a collection of heart development related pathways from Gene Ontology and Mammalian Phenotype Ontology analysis. We then constructed gene regulation networks using unique genes collected from the rCNVs found in the ND-CTRD and DS-CTRD cohorts. These gene networks were clustered and their predicted functions were examined. We further investigated expression patterns of those unique genes using publicly available mouse embryo microarray expression data from single-cell embryos to fully developed hearts. By these bioinformatics approaches, we identified a commonly shared gene expression pattern in both the ND-CTRD and DS-CTRD cohorts. Computational analysis of gene functions characterized with this expression pattern revealed a collection of significantly enriched terms related to cardiovascular development. By our combined analysis of rCNVs in the ND-CTRD and DS-CTRD cohorts, a group of statistically significant shared pathways, biological functions, and gene expression patterns were identified that can be tested in future studies for their biological relevance.
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http://dx.doi.org/10.1002/bdr2.1534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7398559PMC
August 2019

Molecular genetics of 22q11.2 deletion syndrome.

Am J Med Genet A 2018 10;176(10):2070-2081

Institute of Child Health, University College London, London, UK.

The 22q11.2 deletion syndrome (22q11.2DS) is a congenital malformation and neuropsychiatric disorder caused by meiotic chromosome rearrangements. One of the goals of this review is to summarize the current state of basic research studies of 22q11.2DS. It highlights efforts to understand the mechanisms responsible for the 22q11.2 deletion that occurs in meiosis. This mechanism involves the four sets of low copy repeats (LCR22) that are dispersed in the 22q11.2 region and the deletion is mediated by nonallelic homologous recombination events. This review also highlights selected genes mapping to the 22q11.2 region that may contribute to the typical clinical findings associated with the disorder and explain that mutations in genes on the remaining allele can uncover rare recessive conditions. Another important aspect of 22q11.2DS is the existence of phenotypic heterogeneity. While some patients are mildly affected, others have severe medical, cognitive, and/or psychiatric challenges. Variability may be due in part to the presence of genetic modifiers. This review discusses current genome-wide efforts to identify such modifiers that could shed light on molecular pathways required for normal human development, cognition or behavior.
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http://dx.doi.org/10.1002/ajmg.a.40504DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6214629PMC
October 2018

NOTCH maintains developmental cardiac gene network through WNT5A.

J Mol Cell Cardiol 2018 12 19;125:98-105. Epub 2018 Oct 19.

Departments of Genetics, Pediatrics, and Medicine (Cardiology), Albert Einstein College of Medicine, Institute for Aging Research, Wilf Cardiovascular Research Institute, New York 10461, USA; Department of Cardiology of First Affiliated Hospital, State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu, China. Electronic address:

NOTCH and WNT signaling pathways play critical roles in cardiac chamber formation. Here we explored the potential interactions between the two pathways in this developmental process by using genetically modified mouse models and whole embryo culture systems. By deletion of Notch1 to inactivate NOTCH1 signaling in the endocardium in vivo and ex vivo rescue experiments, we showed that myocardial WNT5A mediated endocardial NOTCH1 signaling to maintain the gene regulatory network essential for cardiac chamber formation. Furthermore, genetic deletion of β-catenin in the myocardium and inhibition of the WNT/Ca signaling by FK506 resulted in a similar disruption of the gene regulatory network as inactivation of endocardial NOTCH1 signaling. Together, these findings identify WNT5A as a key myocardial factor that mediates the endocardial NOTCH signaling to maintain the gene regulatory network essential for cardiac chamber formation through WNT/β-catenin and WNT/Ca signaling pathways.
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http://dx.doi.org/10.1016/j.yjmcc.2018.10.014DOI Listing
December 2018

The Prevalence of Ultrarapid Metabolizers of Codeine in a Diverse Urban Population.

Otolaryngol Head Neck Surg 2019 03 16;160(3):420-425. Epub 2018 Oct 16.

2 Albert Einstein College of Medicine, Bronx, NY, USA.

Objective: To examine the prevalence of ultrarapid metabolizers of codeine among children in an ethnically diverse urban community.

Study Design: Cross-sectional study.

Setting: A tertiary care academic children's hospital in the Bronx, New York.

Subjects And Methods: In total, 256 children with nonsyndromic congenital sensorineural hearing loss were analyzed. DNA was assessed for 63 previously described single-nucleotide polymorphisms (SNPs) and copy number variants (CNVs) known to alter the function and expression of the CYP2D6 gene primarily responsible for codeine metabolism. The rate of CYP2D6 metabolism was predicted based on participants' haplotype.

Results: Ethnic distribution in the study subjects paralleled recent local census data, with the largest portion (115 children, 45.8%) identified as Hispanic or Latino. A total of 154 children (80.6%) had a haplotype that corresponds to extensive codeine metabolism, 18 children (9.42%) were identified as ultrarapid metabolizers (UMs), and 16 children (8.37%) were intermediate metabolizers. Only 3 children in our cohort (1.57%) were poor metabolizers. Patients identifying as Caucasian or Hispanic had an elevated incidence of UMs (11.3% and 11.2%, respectively) with extensive variability within subpopulations.

Conclusions: The clinically significant rate of ultrarapid metabolizers reinforces safety concerns regarding the use of codeine and related opiates. A patient-targeted approach using pharmacogenomics may mitigate adverse effects by individualizing the selection and dosing of these analgesics.
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http://dx.doi.org/10.1177/0194599818804780DOI Listing
March 2019

Variance of IQ is partially dependent on deletion type among 1,427 22q11.2 deletion syndrome subjects.

Am J Med Genet A 2018 10 5;176(10):2172-2181. Epub 2018 Oct 5.

Department of Genetics, Albert Einstein College of Medicine, Bronx, New York.

The 22q11.2 deletion syndrome is caused by non-allelic homologous recombination events during meiosis between low copy repeats (LCR22) termed A, B, C, and D. Most patients have a typical LCR22A-D (AD) deletion of 3 million base pairs (Mb). In this report, we evaluated IQ scores in 1,478 subjects with 22q11.2DS. The mean of full scale IQ, verbal IQ, and performance IQ scores in our cohort were 72.41 (standard deviation-SD of 13.72), 75.91(SD of 14.46), and 73.01(SD of 13.71), respectively. To investigate whether IQ scores are associated with deletion size, we examined individuals with the 3 Mb, AD (n = 1,353) and nested 1.5 Mb, AB (n = 74) deletions, since they comprised the largest subgroups. We found that full scale IQ was decreased by 6.25 points (p = .002), verbal IQ was decreased by 8.17 points (p = .0002) and performance IQ was decreased by 4.03 points (p = .028) in subjects with the AD versus AB deletion. Thus, individuals with the smaller, 1.5 Mb AB deletion have modestly higher IQ scores than those with the larger, 3 Mb AD deletion. Overall, the deletion of genes in the AB region largely explains the observed low IQ in the 22q11.2DS population. However, our results also indicate that haploinsufficiency of genes in the LCR22B-D region (BD) exert an additional negative impact on IQ. Furthermore, we did not find evidence of a confounding effect of severe congenital heart disease on IQ scores in our cohort.
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http://dx.doi.org/10.1002/ajmg.a.40359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6209529PMC
October 2018

Dysregulation of TBX1 dosage in the anterior heart field results in congenital heart disease resembling the 22q11.2 duplication syndrome.

Hum Mol Genet 2018 06;27(11):1847-1857

Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.

Non-allelic homologous recombination events on chromosome 22q11.2 during meiosis can result in either the deletion (22q11.2DS) or duplication (22q11.2DupS) syndrome. Although the spectrum and frequency of congenital heart disease (CHD) are known for 22q11.2DS, there is less known for 22q11.2DupS. We now evaluated cardiac phenotypes in 235 subjects with 22q11.2DupS including 102 subjects we collected and 133 subjects that were previously reported as a confirmation and found 25% have CHD, mostly affecting the cardiac outflow tract (OFT). Previous studies have shown that global loss or gain of function (LOF; GOF) of mouse Tbx1, encoding a T-box transcription factor mapping to the region of synteny to 22q11.2, results in similar OFT defects. To further evaluate Tbx1 function in the progenitor cells forming the cardiac OFT, termed the anterior heart field, Tbx1 was overexpressed using the Mef2c-AHF-Cre driver (Tbx1 GOF). Here we found that all resulting conditional GOF embryos had a persistent truncus arteriosus (PTA), similar to what was previously reported for conditional Tbx1 LOF mutant embryos. To understand the basis for the PTA in the conditional GOF embryos, we found that proliferation in the Mef2c-AHF-Cre lineage cells before migrating to the heart, was reduced and critical genes were oppositely changed in this tissue in Tbx1 GOF embryos versus conditional LOF embryos. These results suggest that a major function of TBX1 in the AHF is to maintain the normal balance of expression of key cardiac developmental genes required to form the aorta and pulmonary trunk, which is disrupted in 22q11.2DS and 22q11.2DupS.
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http://dx.doi.org/10.1093/hmg/ddy078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5961083PMC
June 2018

Deletion size analysis of 1680 22q11.2DS subjects identifies a new recombination hotspot on chromosome 22q11.2.

Hum Mol Genet 2018 04;27(7):1150-1163

Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA.

Recurrent, de novo, meiotic non-allelic homologous recombination events between low copy repeats, termed LCR22s, leads to the 22q11.2 deletion syndrome (22q11.2DS; velo-cardio-facial syndrome/DiGeorge syndrome). Although most 22q11.2DS patients have a similar sized 3 million base pair (Mb), LCR22A-D deletion, some have nested LCR22A-B or LCR22A-C deletions. Our goal is to identify additional recurrent 22q11.2 deletions associated with 22q11.2DS, serving as recombination hotspots for meiotic chromosomal rearrangements. Here, using data from Affymetrix 6.0 microarrays on 1680 22q11.2DS subjects, we identified what appeared to be a nested proximal 22q11.2 deletion in 38 (2.3%) of them. Using molecular and haplotype analyses from 14 subjects and their parent(s) with available DNA, we found essentially three types of scenarios to explain this observation. In eight subjects, the proximal breakpoints occurred in a small sized 12 kb LCR distal to LCR22A, referred to LCR22A+, resulting in LCR22A+-B or LCR22A+-D deletions. Six of these eight subjects had a nested 22q11.2 deletion that occurred during meiosis in a parent carrying a benign 0.2 Mb duplication of the LCR22A-LCR22A+ region with a breakpoint in LCR22A+. Another six had a typical de novo LCR22A-D deletion on one allele and inherited the LCR22A-A+ duplication from the other parent thus appearing on microarrays to have a nested deletion. LCR22A+ maps to an evolutionary breakpoint between mice and humans and appears to serve as a local hotspot for chromosome rearrangements on 22q11.2.
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http://dx.doi.org/10.1093/hmg/ddy028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6059186PMC
April 2018

Integrated rare variant-based risk gene prioritization in disease case-control sequencing studies.

PLoS Genet 2017 12 27;13(12):e1007142. Epub 2017 Dec 27.

Department of Genetics, Albert Einstein College of Medicine, Bronx, New York, United States of America.

Rare variants of major effect play an important role in human complex diseases and can be discovered by sequencing-based genome-wide association studies. Here, we introduce an integrated approach that combines the rare variant association test with gene network and phenotype information to identify risk genes implicated by rare variants for human complex diseases. Our data integration method follows a 'discovery-driven' strategy without relying on prior knowledge about the disease and thus maintains the unbiased character of genome-wide association studies. Simulations reveal that our method can outperform a widely-used rare variant association test method by 2 to 3 times. In a case study of a small disease cohort, we uncovered putative risk genes and the corresponding rare variants that may act as genetic modifiers of congenital heart disease in 22q11.2 deletion syndrome patients. These variants were missed by a conventional approach that relied on the rare variant association test alone.
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http://dx.doi.org/10.1371/journal.pgen.1007142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5760082PMC
December 2017

Genome-Wide Association Study to Find Modifiers for Tetralogy of Fallot in the 22q11.2 Deletion Syndrome Identifies Variants in the Locus on 5q14.3.

Circ Cardiovasc Genet 2017 Oct;10(5)

From the Department of Genetics (T.G., J.H.C., H.N., C.L.C., T.W., B.E.M.) and Department of Epidemiology and Population Health (T.W.), Albert Einstein College of Medicine, Bronx, NY; Center for Human Genetics, Facultad de Medicina Clinica Alemana Universidad del Desarrollo, Santiago, Chile (G.M.R.); Division of Human Genetics (D.M.M.M., E.E.M., E.Z., B.S.E.), Division of Cardiology (E.G.), and Department of Pediatrics (E.G.), Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia; Department of Genetics, Wroclaw Medical University, Poland (A.B.); Clinical Genetics Research Program, Center for Addiction and Mental Health and Department of Psychiatry, University of Toronto (A.S.B., E.W.C.C.); Dalglish Family 22q Clinic, Department of Psychiatry and Toronto General Research Institute, University Health Network, Canada (A.S.B.); Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Canada (A.S.B.); Center for Human Genetics, University of Leuven (KU Leuven), Belgium (A.S., J.V., K.D.); The Child Psychiatry Division, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel (D.G.); Sackler Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University, Israel (D.G., M.C., E.M.); Felsenstein Medical Research Center, Sackler Faculty of Medicine, Tel Aviv University, Petah Tikva, Israel (M.C., E.M.); Developmental Imaging and Psychopathology Lab, University of Geneva School of Medicine, Switzerland (M.S., S.E.); Department of Genetic Medicine, UNIGE and iGE3 Institute of Genetics and Genomics of Geneva, University of Geneva Medical Center, Switzerland (S.E.A.); Marcus Autism Center, Children's Healthcare of Atlanta, GA (K.C.); Division of Pediatric Cardiovascular Surgery, Children's Hospital of Wisconsin, Milwaukee (A.T.-M., M.E.M.); Department of Surgery, Medical College of Wisconsin, Milwaukee (A.T.-M., M.E.M.); Department of Medical Genetics, Bambino Gesù Hospital, Rome, Italy (M.C.D., B.D.); Department of Pediatrics, La Sapienza University of Rome, Italy (B.M.); Department of Medical Genetics, Aix Marseille University, APHM, GMGF, Timone Hospital, France (N.P., T.B.); Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, University of California at Los Angeles (L.K.-W., C.E.B.); Department of Genetics, Polish Mother's Memorial Hospital, Research Institute, Łódź, Poland (M.P., W.H.); Department of Cardiology and Division of Genetics, Boston Children's Hospital, MA (A.E.R.); M.I.N.D. Institute and Department of Psychiatry and Behavioral Sciences (F.T.) and M.I.N.D. Institute and Department of Biochemistry and Molecular Medicine (T.J.S.), University of California, Davis; Department of Psychiatry and Psychology, University of Maastricht, The Netherlands (E.D.A.V.D., T.A.v.A.); Department of Psychiatry and Behavioral Sciences, and Program in Neuroscience, SUNY Upstate Medical University, Syracuse, NY (T.A.v.A., W.R.K.); Department of Human Genetics, Emory University School of Medicine, Atlanta, GA (H.R.J., D.J.C.); Department of Biostatistics and Bioinformatics, Emory University Rollins School of Public Health, Atlanta, GA (H.R.J.); and Human Genetics Center and Department of Epidemiology, Human Genetics and Environmental Sciences, UTHealth School of Public Health, Houston, TX (A.J.A., L.E.M.).

Background: The 22q11.2 deletion syndrome (22q11.2DS; DiGeorge syndrome/velocardiofacial syndrome) occurs in 1 of 4000 live births, and 60% to 70% of affected individuals have congenital heart disease, ranging from mild to severe. In our cohort of 1472 subjects with 22q11.2DS, a total of 62% (n=906) have congenital heart disease and 36% (n=326) of these have tetralogy of Fallot (TOF), comprising the largest subset of severe congenital heart disease in the cohort.

Methods And Results: To identify common genetic variants associated with TOF in individuals with 22q11.2DS, we performed a genome-wide association study using Affymetrix 6.0 array and imputed genotype data. In our cohort, TOF was significantly associated with a genotyped single-nucleotide polymorphism (rs12519770, =2.98×10) in an intron of the adhesion (G-protein-coupled receptor V1) gene on chromosome 5q14.3. There was also suggestive evidence of association between TOF and several additional single-nucleotide polymorphisms in this region. Some genome-wide significant loci in introns or noncoding regions could affect regulation of genes nearby or at a distance. On the basis of this possibility, we examined existing Hi-C chromatin conformation data to identify genes that might be under shared transcriptional regulation within the region on 5q14.3. There are 6 genes in a topologically associated domain of chromatin with , including (Myocyte-specific enhancer factor 2C). is the only gene that is known to affect heart development in mammals and might be of interest with respect to 22q11.2DS.

Conclusions: In conclusion, common variants may contribute to TOF in 22q11.2DS and may function in cardiac outflow tract development.
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http://dx.doi.org/10.1161/CIRCGENETICS.116.001690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5647121PMC
October 2017

Nested Inversion Polymorphisms Predispose Chromosome 22q11.2 to Meiotic Rearrangements.

Am J Hum Genet 2017 Oct 28;101(4):616-622. Epub 2017 Sep 28.

Department of Human Genetics, Katholieke Universiteit Leuven, Leuven, Belgium. Electronic address:

Inversion polymorphisms between low-copy repeats (LCRs) might predispose chromosomes to meiotic non-allelic homologous recombination (NAHR) events and thus lead to genomic disorders. However, for the 22q11.2 deletion syndrome (22q11.2DS), the most common genomic disorder, no such inversions have been uncovered as of yet. Using fiber-FISH, we demonstrate that parents transmitting the de novo 3 Mb LCR22A-D 22q11.2 deletion, the reciprocal duplication, and the smaller 1.5 Mb LCR22A-B 22q11.2 deletion carry inversions of LCR22B-D or LCR22C-D. Hence, the inversions predispose chromosome 22q11.2 to meiotic rearrangements and increase the individual risk for transmitting rearrangements. Interestingly, the inversions are nested or flanking rather than coinciding with the deletion or duplication sizes. This finding raises the possibility that inversions are a prerequisite not only for 22q11.2 rearrangements but also for all NAHR-mediated genomic disorders.
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http://dx.doi.org/10.1016/j.ajhg.2017.09.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5630191PMC
October 2017

and act in concert to modulate the fate of neurosensory cells of the mouse otic vesicle.

Biol Open 2017 Oct 15;6(10):1472-1482. Epub 2017 Oct 15.

Department of Genetics, Albert Einstein College of Medicine, 1301 Morris Park Avenue, Bronx, NY 10461, USA

The domain within the otic vesicle (OV) known as the neurosensory domain (NSD), contains cells that will give rise to the hair and support cells of the otic sensory organs, as well as the neurons that form the cochleovestibular ganglion (CVG). The molecular dynamics that occur at the NSD boundary relative to adjacent OV cells is not well defined. The transcription factor gene expression pattern is complementary to the NSD, and inactivation results in expansion of the NSD and expression of the Notch ligand, Jag1 mapping, in part of the NSD. To shed light on the role of in NSD development, as well as to test whether and might genetically interact to regulate this process, we inactivated within the expression domain using a knock-in allele. We observed an enlarged neurogenic domain marked by a synergistic increase in expression of and other proneural transcription factor genes in double and conditional loss-of-function embryos. We noted that neuroblasts preferentially expanded across the medial-lateral axis and that an increase in cell proliferation could not account for this expansion, suggesting that there was a change in cell fate. We also found that inactivation of with resulted in failed development of the cristae and semicircular canals, as well as notably fewer hair cells in the ventral epithelium of the inner ear rudiment when inactivated on a null background, compared to mutant embryos. We propose that loss of expression of and within the expression domain tips the balance of cell fates in the NSD, resulting in an overproduction of neuroblasts at the expense of non-neural cells within the OV.
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http://dx.doi.org/10.1242/bio.027359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5665468PMC
October 2017

Rare Genome-Wide Copy Number Variation and Expression of Schizophrenia in 22q11.2 Deletion Syndrome.

Am J Psychiatry 2017 11 28;174(11):1054-1063. Epub 2017 Jul 28.

From the Dalglish Family 22q Clinic, Department of Psychiatry, University Health Network, Toronto; the Department of Psychiatry and Toronto General Research Institute, University Health Network, Toronto; the Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto; the Department of Psychiatry, University of Toronto, Toronto; the Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto; the Centre for Applied Genomics and Program in Genetics and Genome Biology, the Hospital for Sick Children, Toronto; the Medical Genetics Residency Training Program, University of Toronto, Toronto; the Department of Psychiatry and Psychology, Maastricht University, Maastricht, the Netherlands; the Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia; the Departments of Pediatrics and of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia; the Centre for Human Genetics, University of Leuven (KU Leuven), Leuven, Belgium; the Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, Wales; the Department of Psychiatry, Royal College of Surgeons in Ireland, Dublin; the Department of Child and Adolescent Psychiatry, King's College London; the Department of Psychiatry, Tel Aviv University, Tel Aviv, Israel; the Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, UCLA, Los Angeles; Office Médico-Pédagogique Research Unit, Department of Psychiatry, University of Geneva School of Medicine, Geneva; the Department of Psychiatry and Behavioral Sciences, Upstate Medical University, State University of New York, Syracuse; Département de Génétique Médicale, Centre Hospitalier Universitaire de Marseille - Hôpital de la Timone, Marseilles, France; the Department of Pediatrics, Duke University, Durham, N.C.; the Department of Psychology, University of Newcastle, Newcastle, Australia; the Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands; the Department of Human Genetics, Emory University, Atlanta; Centro de Genética y Genómica, Facultad de Medicina, Clínica Alemana Universidad del Desarrollo, Santiago, Chile; the Department of Psychiatry and Behavioral Sciences, UC Davis, Sacramento, Calif.; Molecular Genetics and McLaughlin Centre, and Laboratory Medicine and Pathobiology, University of Toronto, Toronto; the Department of Genetics, Albert Einstein College of Medicine, Bronx, N.Y.; and Genome Diagnostics, Department of Paediatric Laboratory Medicine, the Hospital for Sick Children, Toronto.

Objective: Chromosome 22q11.2 deletion syndrome (22q11.2DS) is associated with a more than 20-fold increased risk for developing schizophrenia. The aim of this study was to identify additional genetic factors (i.e., "second hits") that may contribute to schizophrenia expression.

Method: Through an international consortium, the authors obtained DNA samples from 329 psychiatrically phenotyped subjects with 22q11.2DS. Using a high-resolution microarray platform and established methods to assess copy number variation (CNV), the authors compared the genome-wide burden of rare autosomal CNV, outside of the 22q11.2 deletion region, between two groups: a schizophrenia group and those with no psychotic disorder at age ≥25 years. The authors assessed whether genes overlapped by rare CNVs were overrepresented in functional pathways relevant to schizophrenia.

Results: Rare CNVs overlapping one or more protein-coding genes revealed significant between-group differences. For rare exonic duplications, six of 19 gene sets tested were enriched in the schizophrenia group; genes associated with abnormal nervous system phenotypes remained significant in a stepwise logistic regression model and showed significant interactions with 22q11.2 deletion region genes in a connectivity analysis. For rare exonic deletions, the schizophrenia group had, on average, more genes overlapped. The additional rare CNVs implicated known (e.g., GRM7, 15q13.3, 16p12.2) and novel schizophrenia risk genes and loci.

Conclusions: The results suggest that additional rare CNVs overlapping genes outside of the 22q11.2 deletion region contribute to schizophrenia risk in 22q11.2DS, supporting a multigenic hypothesis for schizophrenia. The findings have implications for understanding expression of psychotic illness and herald the importance of whole-genome sequencing to appreciate the overall genomic architecture of schizophrenia.
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http://dx.doi.org/10.1176/appi.ajp.2017.16121417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5665703PMC
November 2017

Reduced dosage of β-catenin provides significant rescue of cardiac outflow tract anomalies in a Tbx1 conditional null mouse model of 22q11.2 deletion syndrome.

PLoS Genet 2017 03 27;13(3):e1006687. Epub 2017 Mar 27.

Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, United States of America.

The 22q11.2 deletion syndrome (22q11.2DS; velo-cardio-facial syndrome; DiGeorge syndrome) is a congenital anomaly disorder in which haploinsufficiency of TBX1, encoding a T-box transcription factor, is the major candidate for cardiac outflow tract (OFT) malformations. Inactivation of Tbx1 in the anterior heart field (AHF) mesoderm in the mouse results in premature expression of pro-differentiation genes and a persistent truncus arteriosus (PTA) in which septation does not form between the aorta and pulmonary trunk. Canonical Wnt/β-catenin has major roles in cardiac OFT development that may act upstream of Tbx1. Consistent with an antagonistic relationship, we found the opposite gene expression changes occurred in the AHF in β-catenin loss of function embryos compared to Tbx1 loss of function embryos, providing an opportunity to test for genetic rescue. When both alleles of Tbx1 and one allele of β-catenin were inactivated in the Mef2c-AHF-Cre domain, 61% of them (n = 34) showed partial or complete rescue of the PTA defect. Upregulated genes that were oppositely changed in expression in individual mutant embryos were normalized in significantly rescued embryos. Further, β-catenin was increased in expression when Tbx1 was inactivated, suggesting that there may be a negative feedback loop between canonical Wnt and Tbx1 in the AHF to allow the formation of the OFT. We suggest that alteration of this balance may contribute to variable expressivity in 22q11.2DS.
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http://dx.doi.org/10.1371/journal.pgen.1006687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5386301PMC
March 2017

Genetic Drivers of Kidney Defects in the DiGeorge Syndrome.

N Engl J Med 2017 02 25;376(8):742-754. Epub 2017 Jan 25.

From the Division of Nephrology (E.L.-R., M.V., V.P.C., Z.Y., A.M., J.M., N.J.S., D.A.F., R.D., M.W., G.S.M., M.B., J.M.B., K.K., A.G.G., S.S.-C.) and the Division of Nephrology in Medicine and Zuckerman Mind Brain Behavior Institute (B.H.), the Departments of Systems Biology (D.S.P., B.H.), Biochemistry and Molecular Biophysics (B.H.), and Pathology (V.D.), and the Howard Hughes Medical Institute (D.S.P., B.H.), Columbia University, and the Department of Genetics and Development, Columbia University Medical Center (Q.L., V.E.P.), New York, and the Department of Genetics, Albert Einstein College of Medicine, Bronx (S.E.R., B.E.M.) - all in New York; the Center for Human Disease Modeling, Duke University, Durham, NC (Y.P.L., B.R.A., N. Katsanis); the Departments of Internal Medicine-Nephrology (E.A.O.) and Pediatrics-Nephrology (M.G.S., C.E.G., V.V.-W.), University of Michigan School of Medicine, Ann Arbor; the Department of Anatomy, Histology, and Embryology, School of Medicine, University of Split (K.V., M.S.-B.), and the Departments of Pediatrics (A.A., M. Saraga) and Pathology (N. Kunac), University Hospital of Split, Split, Croatia; the Department of Pediatric Nephrology, VU University Medical Center, Amsterdam (R.W., J.A.E.W.); the Department of Medicine, Boston Children's Hospital (A.V., F.H.), and Harvard Medical School, Boston (A.V., F.H., I.A.D.), and the Nephrology Division, Massachusetts General Hospital, Charlestown (I.A.D.) - all in Massachusetts; the Division of Nephrology, Dialysis, Transplantation, and Laboratory on Pathophysiology of Uremia, Istituto G. Gaslini, Genoa (M.B., A.C., G.M.G.), the Department of Clinical and Experimental Medicine, University of Parma (M.B., M. Maiorana, L.A.), and the Pediatric Surgery Unit, University Hospital of Parma (E.C.), Parma, the Section of Nephrology, Department of Emergency and Organ Transplantation, University of Bari, Bari (L.G.), the Department of Medical Sciences, University of Milano, and Institute of Biomedical Technologies, Italian National Institute of Research ITB-CNR, Milan (D.C.), and Dipartimento Ostetrico-Ginecologico e Seconda Divisione di Nefrologia ASST Spedali Civili e Presidio di Montichiari (C.I.) and Cattedra di Nefrologia, Università di Brescia, Seconda Divisione di Nefrologia Azienda Ospedaliera Spedali Civili di Brescia Presidio di Montichiari (F.S.), Brescia - all in Italy; the Department of General and Transplant Surgery, University Hospital of Heidelberg, Germany (V.J.L.); the Department of Pediatric Nephrology, Centre de Référence des Maladies Rénales Héréditaires de l'Enfant et de l'Adulte (R.S., L.H., C.J.), INSERM UMR 1163, Laboratory of Hereditary Kidney Diseases (R.S.), Necker-Enfants Malades Hospital, Paris Descartes-Sorbonne Paris Cite University, Imagine Institute (R.S.), Sorbonne Universités, UPMC 06, Plateforme Post-génomique de la Pitié-Salpêtrière, UMS 2 Omique, Inserm US029 (W.C.), Paris, and the Department of Genetics, Centre Hospitalier Universitaire de Reims, Unité de Formation et de Recherche de Médecine, Reims (D.G.) - both in France; the Department of Neurology, University of Washington School of Medicine, and Northwest VA Parkinson's Disease Research, Education and Clinical Centers, Seattle (A. Samii); the Division of Human Genetics, Department of Pediatrics, 22q and You Center, Children's Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania (D.M.M.-M., T.B.C., E.H.Z., S.L.F.), Division of Nephrology, Children's Hospital of Philadelphia (S.L.F.), and the Department of Genetics, University of Pennsylvania (H.H.), Philadelphia; the Dialysis Unit, Jagiellonian University Medical College (D.D.), and the Department of Pediatric Nephrology, Jagiellonian University Medical College (M. Miklaszewska), Krakow, the Department of Pediatrics, Immunology and Nephrology, Polish Mother's Memorial Hospital Research Institute, Lodz (M.T.), the Department of Pediatric Nephrology Medical University of Lublin, Lublin (P.S.), the Department of Pediatrics, School of Medicine with the Division of Dentistry in Zabrze, Medical University of Silesia, Katowice (M. Szczepanska), the Department of Pediatrics and Nephrology, Medical University of Warsaw, Warsaw (M.M.-W., G.K., A. Szmigielska), and Krysiewicza Children's Hospital (M.Z.) and the Department of Medical Genetics, Poznan University of Medical Sciences, and Center for Medical Genetics GENESIS (A.L.-B., A.M.-K.), Poznań - all in Poland; the Department of Clinical Genetics (J.M.D., D.B.), National Children's Research Centre (J.M.D., P.P.), and University College Dublin School of Medicine (D.B.), Our Lady's Children's Hospital Crumlin, and the National Children's Hospital Tallaght (P.P.), Dublin, Ireland; the Division of Pediatric Nephrology, Children's Mercy Hospital, Kansas City, MO (B.A.W.); University Children's Hospital, Medical Faculty of Skopje, Skopje, Macedonia (Z.G., V.T.); Faculty of Medicine, Palacky University, Olomouc, Czech Republic (H.F.); the Division of Pediatric Nephrology, University of New Mexico Children's Hospital, Albuquerque (C.S.W.); Ben May Department for Cancer Research, University of Chicago, Chicago (A.I.); and the Department of Genetics, Howard Hughes Medical Institute, and Yale Center for Mendelian Genomics, Yale University, New Haven, CT (R.P.L.).

Background: The DiGeorge syndrome, the most common of the microdeletion syndromes, affects multiple organs, including the heart, the nervous system, and the kidney. It is caused by deletions on chromosome 22q11.2; the genetic driver of the kidney defects is unknown.

Methods: We conducted a genomewide search for structural variants in two cohorts: 2080 patients with congenital kidney and urinary tract anomalies and 22,094 controls. We performed exome and targeted resequencing in samples obtained from 586 additional patients with congenital kidney anomalies. We also carried out functional studies using zebrafish and mice.

Results: We identified heterozygous deletions of 22q11.2 in 1.1% of the patients with congenital kidney anomalies and in 0.01% of population controls (odds ratio, 81.5; P=4.5×10). We localized the main drivers of renal disease in the DiGeorge syndrome to a 370-kb region containing nine genes. In zebrafish embryos, an induced loss of function in snap29, aifm3, and crkl resulted in renal defects; the loss of crkl alone was sufficient to induce defects. Five of 586 patients with congenital urinary anomalies had newly identified, heterozygous protein-altering variants, including a premature termination codon, in CRKL. The inactivation of Crkl in the mouse model induced developmental defects similar to those observed in patients with congenital urinary anomalies.

Conclusions: We identified a recurrent 370-kb deletion at the 22q11.2 locus as a driver of kidney defects in the DiGeorge syndrome and in sporadic congenital kidney and urinary tract anomalies. Of the nine genes at this locus, SNAP29, AIFM3, and CRKL appear to be critical to the phenotype, with haploinsufficiency of CRKL emerging as the main genetic driver. (Funded by the National Institutes of Health and others.).
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http://dx.doi.org/10.1056/NEJMoa1609009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5559731PMC
February 2017

A Pedigree-Based Map of Recombination in the Domestic Dog Genome.

G3 (Bethesda) 2016 Nov 8;6(11):3517-3524. Epub 2016 Nov 8.

Department of Genetics, Albert Einstein College of Medicine, Bronx, New York 10461

Meiotic recombination in mammals has been shown to largely cluster into hotspots, which are targeted by the chromatin modifier PRDM9. The canid family, including wolves and dogs, has undergone a series of disrupting mutations in this gene, rendering inactive. Given the importance of , it is of great interest to learn how its absence in the dog genome affects patterns of recombination placement. We have used genotypes from domestic dog pedigrees to generate sex-specific genetic maps of recombination in this species. On a broad scale, we find that placement of recombination events in dogs is consistent with that in mice and apes, in that the majority of recombination occurs toward the telomeres in males, while female crossing over is more frequent and evenly spread along chromosomes. It has been previously suggested that dog recombination is more uniform in distribution than that of humans; however, we found that recombination in dogs is less uniform than in humans. We examined the distribution of recombination within the genome, and found that recombination is elevated immediately upstream of the transcription start site and around CpG islands, in agreement with previous studies, but that this effect is stronger in male dogs. We also found evidence for positive crossover interference influencing the spacing between recombination events in dogs, as has been observed in other species including humans and mice. Overall our data suggests that dogs have similar broad scale properties of recombination to humans, while fine scale recombination is similar to other species lacking .
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http://dx.doi.org/10.1534/g3.116.034678DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5100850PMC
November 2016

Variant discovery and breakpoint region prediction for studying the human 22q11.2 deletion using BAC clone and whole genome sequencing analysis.

Hum Mol Genet 2016 09 19;25(17):3754-3767. Epub 2016 Jul 19.

Department of Neurology

Velo-cardio-facial syndrome/DiGeorge syndrome/22q11.2 deletion syndrome (22q11.2DS) is caused by meiotic non-allelic homologous recombination events between flanking low copy repeats termed LCR22A and LCR22D, resulting in a 3 million base pair (Mb) deletion. Due to their complex structure, large size and high sequence identity, genetic variation within LCR22s among different individuals has not been well characterized. In this study, we sequenced 13 BAC clones derived from LCR22A/D and aligned them with 15 previously available BAC sequences to create a new genetic variation map. The thousands of variants identified by this analysis were not uniformly distributed in the two LCR22s. Moreover, shared single nucleotide variants between LCR22A and LCR22D were enriched in the Breakpoint Cluster Region pseudogene (BCRP) block, suggesting the existence of a possible recombination hotspot there. Interestingly, breakpoints for atypical 22q11.2 rearrangements have previously been located to BCRPs To further explore this finding, we carried out in-depth analyses of whole genome sequence (WGS) data from two unrelated probands harbouring a de novo 3Mb 22q11.2 deletion and their normal parents. By focusing primarily on WGS reads uniquely mapped to LCR22A, using the variation map from our BAC analysis to help resolve allele ambiguity, and by performing PCR analysis, we infer that the deletion breakpoints were most likely located near or within the BCRP module. In summary, we found a high degree of sequence variation in LCR22A and LCR22D and a potential recombination breakpoint near or within the BCRP block, providing a starting point for future breakpoint mapping using additional trios.
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http://dx.doi.org/10.1093/hmg/ddw221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5216616PMC
September 2016

The Role of mGluR Copy Number Variation in Genetic and Environmental Forms of Syndromic Autism Spectrum Disorder.

Sci Rep 2016 Jan 19;6:19372. Epub 2016 Jan 19.

Children's Hospital of Philadelphia, Department of Pediatrics, Philadelphia, PA 19104 USA.

While abnormal signaling mediated through metabotropic glutamate receptor 5 (mGluR5) is involved in the pathophysiology of Autism Spectrum Disorder (ASD), Fragile X Syndrome and Tuberous Sclerosis, the role of other mGluRs and their associated signaling network genes in syndromic ASD is unknown. This study sought to determine whether mGluR Copy Number Variants (CNV's) were overrepresented in children with syndromic ASD and if mGluR "second hit" confers additional risk for ASD in 22q11.2 Deletion Syndrome (22q11DS). To determine whether mGluR network CNV'S are enriched in syndromic ASD, we examined microarrays from children with ASD (n = 539). Patient categorization (syndromic vs nonsyndromic) was done via blinded medical chart review in mGluR positive and randomly selected mGluR negative cases. 11.5% of ASD had mGluR CNV's vs. 3.2% in controls (p < 0.001). Syndromic ASD was more prevalent in children with mGluR CNVs (74% vs 16%, p < 0.001). A comparison cohort with 22q11DS (n = 25 with ASD, n = 50 without ASD), all haploinsufficient for mGluR network gene RANBP1, were evaluated for "second mGluR hits". 20% with 22q11.2DS + ASD had "second hits" in mGluR network genes vs 2% in 22q11.2DS-ASD (p < 0.014). We propose that altered RANBP1 expression may provide a mechanistic link for several seemingly unrelated genetic and environmental forms of ASD.
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http://dx.doi.org/10.1038/srep19372DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4726047PMC
January 2016

Rare copy number variants and congenital heart defects in the 22q11.2 deletion syndrome.

Hum Genet 2016 Mar 7;135(3):273-85. Epub 2016 Jan 7.

Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.

The 22q11.2 deletion syndrome (22q11DS; velocardiofacial/DiGeorge syndrome; VCFS/DGS; MIM #192430; 188400) is the most common microdeletion syndrome. The phenotypic presentation of 22q11DS is highly variable; approximately 60-75 % of 22q11DS patients have been reported to have a congenital heart defect (CHD), mostly of the conotruncal type, and/or aortic arch defect. The etiology of the cardiac phenotypic variability is not currently known for the majority of patients. We hypothesized that rare copy number variants (CNVs) outside the 22q11.2 deleted region may modify the risk of being born with a CHD in this sensitized population. Rare CNV analysis was performed using Affymetrix SNP Array 6.0 data from 946 22q11DS subjects with CHDs (n = 607) or with normal cardiac anatomy (n = 339). Although there was no significant difference in the overall burden of rare CNVs, an overabundance of CNVs affecting cardiac-related genes was detected in 22q11DS individuals with CHDs. When the rare CNVs were examined with regard to gene interactions, specific cardiac networks, such as Wnt signaling, appear to be overrepresented in 22q11DS CHD cases but not 22q11DS controls with a normal heart. Collectively, these data suggest that CNVs outside the 22q11.2 region may contain genes that modify risk for CHDs in some 22q11DS patients.
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http://dx.doi.org/10.1007/s00439-015-1623-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4896312PMC
March 2016

Genetic analysis of nonalcoholic fatty liver disease within a Caribbean-Hispanic population.

Mol Genet Genomic Med 2015 Nov 11;3(6):558-69. Epub 2015 Aug 11.

Department of GeneticsAlbert Einstein College of Medicine1301 Morris Park Ave.BronxNew York10461; Department of Anatomy and Structural BiologyAlbert Einstein College of MedicineBronxNew York10461.

We explored potential genetic risk factors implicated in nonalcoholic fatty liver disease (NAFLD) within a Caribbean-Hispanic population in New York City. A total of 316 individuals including 40 subjects with biopsy-proven NAFLD, 24 ethnically matched non-NAFLD controls, and a 252 ethnically mixed random sampling of Bronx County, New York were analyzed. Genotype analysis was performed to determine allelic frequencies of 74 known single-nucleotide polymorphisms (SNPs) associated with NAFLD risk based on previous genome-wide association study (GWAS) and candidate gene studies. Additionally, the entire coding region of PNPLA3, a gene showing the strongest association to NAFLD was subjected to Sanger sequencing. Results suggest that both rare and common DNA variations in PNPLA3 and SAMM50 may be correlated with NAFLD in this small population study, while common DNA variations in CHUK and ERLIN1, may have a protective interaction. Common SNPs in ENPP1 and ABCC2 have suggestive association with fatty liver, but with less compelling significance. In conclusion, Hispanic patients of Caribbean ancestry may have different interactions with NAFLD genetic modifiers; therefore, further investigation with a larger sample size, into this Caribbean-Hispanic population is warranted.
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http://dx.doi.org/10.1002/mgg3.168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4694126PMC
November 2015

Histone Modifier Genes Alter Conotruncal Heart Phenotypes in 22q11.2 Deletion Syndrome.

Am J Hum Genet 2015 Dec 19;97(6):869-77. Epub 2015 Nov 19.

Department of Genetics, Albert Einstein College of Medicine, Yeshiva University, Bronx, NY 10461, USA. Electronic address:

We performed whole exome sequence (WES) to identify genetic modifiers on 184 individuals with 22q11.2 deletion syndrome (22q11DS), of whom 89 case subjects had severe congenital heart disease (CHD) and 95 control subjects had normal hearts. Three genes including JMJD1C (jumonji domain containing 1C), RREB1 (Ras responsive element binding protein 1), and SEC24C (SEC24 family member C) had rare (MAF < 0.001) predicted deleterious single-nucleotide variations (rdSNVs) in seven case subjects and no control subjects (p = 0.005; Fisher exact and permutation tests). Because JMJD1C and RREB1 are involved in chromatin modification, we investigated other histone modification genes. Eighteen case subjects (20%) had rdSNVs in four genes (JMJD1C, RREB1, MINA, KDM7A) all involved in demethylation of histones (H3K9, H3K27). Overall, rdSNVs were enriched in histone modifier genes that activate transcription (Fisher exact p = 0.0004, permutations, p = 0.0003, OR = 5.16); however, rdSNVs in control subjects were not enriched. This implicates histone modification genes as influencing risk for CHD in presence of the deletion.
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http://dx.doi.org/10.1016/j.ajhg.2015.10.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4678435PMC
December 2015